Project Summary Primary open angle glaucoma is the second-leading cause of blindness worldwide and is characterized by progressive retinal ganglion cell death and irreversible vision loss. Previous experimental studies have established aspects of the relationship between retinal structure and function, while others have demonstrated correlations between vascular health and glaucoma. However, a unified theory of the structural and hemodynamic factors that combine within tissue to cause visual impairment in glaucoma is missing. The development and use of this innovative combined clinical, mathematical, and statistical modeling approach will elucidate the specific relationships of tissue structure, blood flow and visual field loss. Importantly, glaucomatous changes to structure and function occur in certain segments of the tissue, and our study is designed to demonstrate order and importance of structure, function, and blood flow within specific regions of the retina and optic nerve (ONH). The proposed work will use state-of-the-art imaging techniques to measure structural elements (e.g., ONH parameters including cup-to-disc ratio, and retinal nerve fiber layer thickness), hemodynamic elements (e.g., capillary flow, venous saturation, vessel density), and functional elements (e.g., visual field indices) in healthy and glaucomatous patients. The proposed work will also produce a mathematical model that, for the first time, predicts oxygen transport and blood flow regulation in a realistic heterogeneous description of the retinal microvasculature, yielding spatial predictions of oxygenation that can be used to identify regions of the retina most at risk of functional damage. Finally, a unique combination of statistical and mathematical modeling approaches will be implemented to create functions that describe the dependence of retinal function on structural and hemodynamic factors within specific regions of the retina and ONH. The outcomes of this proposal have the potential for improving diagnostic and treatment strategies and improving the lives of millions of glaucomatous patients worldwide. The specific and novel sectorial analysis proposed in this study is based on a vast collection of clinical and research data that is conducted using non-trivial and highly powerful mathematical tools. Since the individual roles of hemodynamic and structural factors cannot be individually modulated or identified in a clinical setting, this integrated theoretical and clinical approach will lead to breakthroughs in glaucoma management while also advancing the knowledge of mathematical modeling and computational techniques.